ORMDL3 and Asthma: Linking Sphingolipid Regulation to Altered T Cell Function

Abstract

Orosomucoid like 3 (ORMDL3) encodes an ER-resident transmembrane protein that regulates the activity of serine palmitoyltransferase (SPT), the first and rate-limiting enzyme for sphingolipid biosynthesis in cells. A decade ago, several genome wide association studies revealed single nucleotide polymorphisms associated with increased ORMDL3 protein expression and susceptibility to allergic asthma. Since that time, numerous studies have investigated how altered ORMDL3 expression might predispose to asthma and other autoimmune/inflammatory diseases. In this brief review, we focus on growing evidence suggesting that heightened ORMDL3 expression specifically in CD4+ T lymphocytes, the central orchestrators of adaptive immunity, constitutes a major underlying mechanism of asthma pathogenesis by skewing their differentiation and function. Furthermore, we explore how sphingolipid modulation in T cells might be responsible for these effects, and how further studies may interrogate this intriguing hypothesis.

Nasal airway transcriptome-wide association study of asthma reveals genetically driven mucus pathobiology

“…First, while we observed strong COA associations with GSDMB in TWAS analysis of both the nasal airway and blood, for IKZF3 and ORMDL3 , strong COA associations were only observed in either the airway or blood, respectively, but not both. Secondly, although a subset of 17q21 genes have already been implicated in disparate mechanisms of asthma development (e.g., [1] ORMDL3 in sphingolipid homeostasis 22 , 23 and the function of T cells and [2] GSDMB in pyroptosis 19 , 43 ), our results suggest additional involvement of the locus based on our identification of 15 COA-associated genes across the six tissue types examined, including 14 from the airway, of which seven were airway-specific. Among these airway-specific genes was IKZF3 , a transcription factor that is not expressed by airway epithelial cells but has been implicated in T, B, and innate lymphoid cell (ILC) development 24 – 26 .…”

The Role of Sphingolipids in Allergic Disorders

“…Ceramide synthesis also seems to be involved in asthma, based on the increased expression of Orosomucoid-like 3 (ORMDL3), an endoplasmic reticulum (ER)-resident transmembrane protein that regulates the activity of serine palmitoyltransferase (SPT) ( 45 ). It has also been suggested to be involved in ER-mediated calcium signaling and stress response in immune cells ( 46 ); as well as in eosinophil trafficking, recruitment, and degranulation in murine models of allergic asthma ( 47 ).…”

“…This protein acts as a negative regulator of sphingolipid biosynthesis. Its overexpression in the respiratory tract of asthmatic patients promotes CER synthesis and the development of T2 responses in the airways ( 45 , 48 ). The nasal administration of FTY720/fingolimod reduced ORMDL3 expression and CER levels, mitigating the airway inflammation and mucus hypersecretion in house dust mite–challenged mice ( 49 ).…”

Exon variants associated with asthma and allergy1

“…Although ORMDL3 has been repeatedly favored by the Oxford group (10) along with their earlier claim on FcεR1ß/MS4A2 (37), a structural contribution of both genes to asthma and allergy is unlikely. Although evidence of absence is not absence of evidence, there is no further support that blocking MS4A2 or ORMDL3 expression (38) would be beneficial for asthma patients. CYSLTR2, the Tristan da Cunha asthma gene (39) was also not tagged here neither ADAM33 (40).…”